The data reported here show Phaxan™ causes anaesthesia with fast onset, and offset timing equal with propofol. Phaxan™ is twice as potent as propofol. It is a clear water-soluble preparation using an FDA-approved excipient to achieve water solubility—sulfobutyl ether beta cyclodextrin. This avoids the only impediment to alphaxalone being used clinically for human anaesthesia in today's operating rooms, i.e. hypersensitivity reactions to CremophorEL in which it was formulated previously (Althesin® 1972-84). This advance will allow the reintroduction of this useful agent into human anaesthetic practice. drawbridge Pharmaceuticals Pty Ltd is currently developing Phaxan™ for use in humans for induction and maintenance of anaesthesia, procedural sedation and sedation in the intensive care unit. Phaxan™ is filterable with none of the infection, manufacturing and lipid toxicity issues associated with propofol lipid formulations. Drawbridge Pharmaceuticals, currently developing Phaxan for clinical use is about to commence Phase 2 trials..

1. ™
PhaxanCD , a Captisol®-enabled water soluble preparation of alphaxalone for in-
™
PhaxanCD , a and sedation:®-enabled waterwith propofol and Al-
travenous anesthesia Captisol comparison of toxicity soluble
Captisol®
preparation of alphaxalone for intravenous anesthesia
thesin®
and sedation: comparison of anesthetic properties
with propofol and Althesin®
Althesin®
1,2 1 3 2
CS Goodchild , A Kolosov , B Boyd , and JM Serrao .
1 Monash Institute of Medical Research, 27-31 Wright Street, Clayton, 3168 Victoria, Australia
2 Goodchild Investments, Suite 200, 45 Glenferrie Rd, Malvern, 3144 Victoria, Australia
3 Faculty of Pharmacy and Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, 3052 Victoria, Australia
Introduction
Alphaxalone is a neuroactive steroid that causes anesthesia by positive modulation at GABAA receptors. It was the main ingredient of Althesin®, used widely
for intravenous anesthesia from 1971 until 1984 when it was withdrawn from clinical practice because of hypersensitivity to Cremophor EL the emulsifying agent
used in the formulation (1). Many attempts have been made to reformulate this compound for human use because of its favourable anesthetic and safety profile but
hitherto those attempts have failed to prepare a suitable water based preparation. Captisol® is 7-sulfobutylether β-cyclodextrin; a molecule with a lipophilic cavity.
that enables water insoluble drug dispersal in water for human use.
COMPLEX DISSOCIATES
Objectives IMMEDIATELY AFTER
1. dissolve alphaxalone in water using Captisol® INTRAVENOUS INJECTION
2. assess anesthesia and recovery using this preparation and
3. compare these properties with propofol and Althesin®
Materials and Methods
A solution of alphaxalone [10mg.ml-1 ;PhaxanCD™ (PHAX)] was prepared by dissolving alphaxalone 300mg (0.9 mmoles) in saline 0.9% 30ml, using Captisol®
(7-sulfobutyl ether beta cyclodextrin) 3889mg (1.8 mmoles); this produced a solution with a complexation ratio alphaxalone:Captisol® of 1:2. An ―Althesin®-like‖
solution of alphaxalone in 20% CremophorEL (ALTH) was prepared as described in the literature (2). Male Wistar rats (wt 150-220g) were implanted with
indwelling internal jugular vein intravenous catheters under halothane anaesthesia. Twenty four hours later each rat received an intravenous injection from a range
of doses of either PHAX or ALTH (1.25, 2.5, 5, 10, & 15 mg.kg-1), or propofol emulsion [10mg.ml-1 propofol; PROP] (1.25, 2.5, 3.75, 5, 10, 15, & 20mg.kg-1); n =
10 rats at each dose. Three more groups of 10 rats each were given vehicle only instead of the anesthetic solutions [13% Captisol®; 20% CremophoEL; 10% lipid
emulsion]. The following were assessed at regular time intervals after the intravenous injection:
 righting reflex: 1 normal; 2 slow; 3 some attempt; 4 none – this was a measure of onset and duration of unconsciousness
 tail pinch response: 1 normal; 2 weak; 3 just present; 4 none – this was a measure of onset and duration of surgical anaesthesia
 time the rat was able to walk on the rotarod (a rotating cylinder) measured in seconds: the maximal normal run time is 120 s in non sedated rats – this
was a measure of time taken to attain full recovery from the sedating effects of the anaesthetic injections
Results from groups of ten rats treated with the same anaesthetic and dose were combined for statistical purposes. Rats that attained a score of 4 for loss of
righting reflex were deemed to have lost consciousness and those that scored a 4 for loss of tail pinch response were deemed to be surgically anaesthetised. The
number of rats in each group of 10 similarly treated animals that scored 4 were subjected to probit regression analysis using SPSS Statistics 18 to produce graphs of
probit value v log dose (probit plot). Those were used to calculate the estimated dose that caused anaesthesia in 50% and 95% of subjects (AD50 and AD95
respectively) for unconsciousness (righting reflex measurements) and surgical anaesthesia (tail pinch responses). The time of onset and recovery of rotarod walking
ability was also plotted for each dose and treatment. This was used as a measurement of complete recovery.
Results
Alphaxalone (10mg.ml-1) dissolved readily in 13% Captisol®-saline solution. The
resultant solution was colourless and completely clear. It did not cause stiction when
used in plastic syringes.
Intravenous PHAX caused immediate dose-related sedation and anesthesia
accompanied by no abnormal movements. The graphs show the probit plots for
anesthetic end points for righting reflex and tail pinch responses. Also shown are
graphs of the mean walking time on the rotarod for groups of 10 rats at each dose of
the three anesthetic preparations.
The table below summarises the results taken from these graphical plots. It can be
seen that PhaxanCD is equipotent with Althesin® in causing unconsciousness and
surgical anaesthesia and both are more potent than propofol in this respect. Recovery
from unconsciousness caused by PhaxanCD is just as fast as with propofol. Control
experiments revealed that the vehicles given alone intravenously, 20% CremophorEL,
10% lipid emulsion and 13% Captisol had no sedating or anaesthetic effects.
Althesin® PhaxanCD propofol
dose causing all 10 rats to lose
5 5 10
righting reflex mg.kg-1
AD50 for loss of righting reflex
2.95 2.79 4.63
mg.kg-1
AD95 for loss of righting reflex
4.39 4.26 8.40
mg.kg-1
AD50 for loss of tail pinch response
6.46 6.56 8.40 Conclusions
reflex mg.kg-1 PhaxanCD™ causes anesthesia with fast onset, and offset timing equal
AD95 for loss of tail pinch response with propofol and Althesin®, the former commercial human anesthetic
14.09 8.56 14.46
mg.kg-1 formulation of alphaxalone.
duration (minutes) of loss of righting PhaxanCD™ is twice as potent as propofol.
reflex at dose causing
3.6 (2.18) 1.9 (0.84) 2.5 (1.15) PhaxanCD™ is a clear water-soluble preparation using an FDA-
all 10 rats to lose righting reflex
approved excipient to achieve water solubility—Captisol®. This avoids
mean (SD)
the only impediment to alphaxalone being used clinically for human
anesthesia in todays operating rooms, i.e., hypersensitivity reactions to
Reference List CremophorEL. This advance will allow the reintroduction of this useful
(1) Prys-Roberts C, Sear J. Steroid anaesthesia. Br J Anaesth 1980 Apr;52(4):363-5. agent into human anesthetic practice.
(2) Davis B, Pearce DR. An introduction to Althesin (CT 1341). Postgrad Med J 1972 PhaxanCD™ is filterable with none of the infection, manufacturing and
Jun;48:Suppl-7. lipid toxicity issues associated with propofol lipid formulations.